Arginine-dependent immune responses

Abstract

A growing body of evidence indicates that, over the course of evolution of the immune system, arginine has been selected as a node for the regulation of immune responses. An appropriate supply of arginine has long been associated with the improvement of immune responses. In addition to being a building block for protein synthesis, arginine serves as a substrate for distinct metabolic pathways that profoundly affect immune cell biology; especially macrophage, dendritic cell and T cell immunobiology. Arginine availability, synthesis, and catabolism are highly interrelated aspects of immune responses and their fine-tuning can dictate divergent pro-inflammatory or anti-inflammatory immune outcomes. Here, we review the organismal pathways of arginine metabolism in humans and rodents, as essential modulators of the availability of this semi-essential amino acid for immune cells. We subsequently review well-established and novel findings on the functional impact of arginine biosynthetic and catabolic pathways on the main immune cell lineages. Finally, as arginine has emerged as a molecule impacting on a plethora of immune functions, we integrate key notions on how the disruption or perversion of arginine metabolism is implicated in pathologies ranging from infectious diseases to autoimmunity and cancer.

Keywords: Arginase; Arginase 1; Arginase 2; Arginine metabolism; Immunity; Immunometabolism; NOS; Nitric oxide synthase.

Fig. 1

Inter-organ arginine metabolism and the intestinal renal arginine synthesis axis

Fig. 2

Overview of pathways involved in arginine metabolism. Abbreviations: ADC arginine decarboxylase, AGAT arginine:glycine amidinotransferase, GAMT guanidinoacetate N-methyltransferase ARG arginase, NOS nitric oxide synthase, ASL argininosuccinate lyase, ODC ornithine decarboxylase, ASS1 argininosuccinate synthase 1, OTC ornithine carbamoyltransferase, SMS spermine synthase, SRM spermidine synthase, P5CS delta–1–pyrroline–5–carboxylate synthase, PYCR pyrroline–5–carboxylate reductase, PYCRL pyrroline–5–carboxylate reductase-like, OAT ornithine aminotransferase

Fig. 3

Overview of the deleterious effects that arginine starvation exerts on T cell functions

Fig. 4

Subcellular localization of proteins involved in arginine metabolism. Abbreviations: ADC arginine decarboxylase, AGAT arginine:glycine amidinotransferase, ARG arginase, NOS2 nitric oxide synthase 2, ASS1 argininosuccinate synthase 1, ASL argininosuccinate lyase, CATs cationic amino acid transporters, GAMT guanidinoacetate N-methyltransferase, OTC ornithine carbamoyltransferase, OAT ornithine aminotransferase